Method for establishing the source of infection in a case of fever of unclear aetiology

ABSTRACT

Use of gene expression profiles obtained in vitro from a patient&#39;s sample for establishing the local infection of a “fever of unknown origin”, wherein the gene expression profiles are specific for local inflammations of a “fever of unknown origin”, such as peritonitis, pneumonia, endocarditis or infections of the urea tract.

The present invention relates to the use of gene expression profiles obtained in vitro from a patient's sample for establishing the local inflammation of a fever of unknown origin according to claim 1, a method for measuring in vitro such gene expression profiles according to claim 14, as well as the use of the gene expression profiles and/or of the probes used therefore for establishing the gene activity or the protein products derived therefrom for the screening of active agents against fever of unknown origin and/or peritonitis and/or pneumonia and/or the evaluation of the therapeutic effects of active agents against fever of unknown origin and/or peritonitis and/or pneumonia according to claim 30, as well as a kit according to claim 33.

Fever of unknown origin (FUO) clinically is defined as a fever with a temperature of more than 38.8° C. lasting over a period of more than 3 weeks, wherein no clear diagnosis regarding the origin could be made after one week of examination. Depending on the origin, there are four classes of FUO described: FUO of classical, nosocomial, immune deficient, or HIV-related origin (1). FUO also was described as rather a known disease with an unusual clinical picture than a rare deficiency (2).

There is neither a gold standard method nor a diagnosis test, there are no published regulations and no evidence based recommendations for the diagnosis of FUO (3). Up to now, the diagnosis of FUO is a challenge and it is made with the aid of the patient's history, of biopsies (e.g. liver, temporal artery), surgical and/or imaging methods such as abdominal computer tomography or nuclear spin imaging methods (3). All these methods are very expensive and unpleasant for the patient (1) because of the surgical intervention (biopsy, surgery). The following 4 subgroups can be defined with regard to the diagnosed main cause: Infection, malignant tumor, autoimmune disorders and other causes, wherein infection is the most frequent cause of FUO (1, 4).

An infection was recorded in only 10% of the patients suffering from post operative fever (5). In most cases, the temperature of the patient returned to normal within four days after the surgical intervention. In spite of this fact, some patients developed an infection on the fifth day after the surgery and 12% of them fell ill to pneumonia (5). Similarly. Pile and his colleagues mentioned that fever occurring two days after the surgery was highly likely triggered by an infection such as, for example, an infection of the urinary tract and/or the inner abdomen (peritonitis), pneumonia, an infection triggered by an intravenous catheter.

Different forms, such as peritonitis, pneumonia, infections of the urea tract or endocarditis (2), can be the local inflammation conditions underlying the FUO. In the following, peritonitis and pneumonia are described, by way of example only, as the inflammation condition underlying FUO.

In an intensive care unit, pneumonia is one of the most severe infectious diseases which may have dramatic effects on the patient's life expectancy (6,7). Pneumonia is an acute or chronic inflammation of the lung parenchyma, which is mostly caused by an infection by bacteria, viruses or fungi. For clinical diagnostics, a difference is made between pneumonia caught in ambulant or nosocomial treatment. 2-3 million cases of pneumonia caused in ambulant treatment were registered in the USA, whereas experts assume that 750.000 cases of ambulant acquired pneumonia occurred in Germany (8). The costs for pneumonia treatment in the USA alone mount up to approx. US$ 8 bn.

Pneumonia is defined as being nosocomial if the pneumonia is diagnosed 48 hours after admission of the patient into the hospital (9). The greatest risk of development of a nosocomially acquired pneumonia in patients in intensive care is caused by the use of ventilators. For this reason, the term ventilator associated pneumonia (VAP) became known for this kind of pneumonia (10). The mortality rate in VAP patients is 30% (10).

According to Saner et al., only 30% of the infections triggered by individual pathogens could be proven in the course of a study of infections caused by surgical operations. According to Sauer, the most common cause of infection in pneumonia was Candida (yeast). In patients suffering from pneumonia, mixed infections with at least two kinds of pathogens (47%), one single pathogen (24%) or no microbes at all (29%) were identified. A possible infection and the resistance is determined on the basis of conventional microbiologic methods of cultivation as well as on resistance tests towards antibiotics (11) and, therefore, underlies the limitations of such methods (non-culturable bacteria, an extended retardation phase due to the administration of antibiotics, etc.).

Peritonitis is a local infection of the peritoneum caused by the entry of bacteria or fungi into the abdominal cavity. Peritoneal mesothelial cells (PMC) in the muscular part of the membrane are interrupted by intermesothelial gaps (stomata) and thus render the contact with the cavities (lacunae) in the lymphatic vessel and the exit of bacteria from the abdominal cavity (12) possible. According to Hall et al. the quick removal of bacteria from the abdominal cavity is an explanation for the initial septic phase of a peritonitis. An infection of the abdominal cavity is dealt with by means of three different mechanisms: 1. Induction of immune defense such as, for example, the release of inflammation mediators, 2. the migration of polymorphonuclear neutrophiles and the complement cascade, and 3. the formation of an abscess.

Usually, peritonitis involves mixed microbial populations (12), however, the outcome of a peritonitis varies depending on the pathogen that has caused the peritonitis (13). Troidle et al., for example, describe that Gram-negative infections lead to a higher mortality and that these patients are more likely to need a hospital stay than in the case of Gram-positive pathogens. In the case of Gram-positive peritonitis, a re-occurrence of the infection at a later time takes place in 32% of the cases, whereas, in comparison, this rate is 9% in the case of Gram-negative peritonitis (9%). In spite of many publications which show the effects of the pathogens on the patient (for example 12), some authors assess the reaction of the host to an infection more important than the infection itself (14). These assessments established from animal models, however, base on a physiologic evaluation system and do not use genomic or proteomic experiments.

New biomolecular methods allow the analysis of the immunologic host response to an infection. Different methods and results are known from the state of the art describing the differential gene activity as response to an disease caused by an infection (15-19).

The basic usability of gene expression profiles which, for example, can be obtained by means of the micro array technology, for the diagnosis of SIRS, generalized inflammatory inflammations, sepsis and severe sepsis, is described in the PCT application of the Applicant of the present invention (20) or (21), which is herein incorporated by reference.

The German patent application (22) shows for the first time gene activity marker for the differentiation between infectious and non-infectious multiple organ failure. This application describes the use of 1.297 different genes for in vitro diagnosis of patients suffering from infectious and non-infectious multiple organ failure, respectively.

It was also possible to show different organ specific studies regarding differential gene expression caused by local inflammations, such as by the examination of lung tissue (19, 23-25) or by examination of changed gene activity of liver tissue in response to faecal peritonitis (26). The tests, however, always related to tissue-specific changes in gene activity, and are, thus, not suitable for establishing a FUO by means of measurement of the gene activity in body fluids.

In the patent application (27) the gene expression is used for establishing the infectious and non-infectious condition of the identified source of infection and it is not used for determining the source of infection. In order to determine, for example, whether there exists an infection in the knee joint, a biopsy is carried out and the cells contained in the synovial fluid are analyzed. This invention does not teach the examination of the differential gene activity in body fluids for establishing the underlying local inflammation of a FUO.

Both Reinhart et al. (28) and the not yet prepublished German patent application (29) of the Applicant of the present invention (28), presented gene expression profiles obtained from whole blood of patients in which SIRS and Sepsis, respectively, were diagnosed. The differential gene activity was used in order to evaluate whether gene activity classificators can differentiate between infectious and non-infectious inflammatory diseases. In this study, the experimentally ascertained gene activity classificators were subsequently compared to the clinical parameters available from the patients. It was shown that the identified gene activity classificators are able to well differentiate between infectious and non-infectious conditions if the clinical data pointed to a peritonitis as underlying local inflammation. The ability to differentiate between infectious and non-infectious conditions, however, was reduced when the clinical data indicated a ventilator-associated pneumonia (VAP). The gene activity classificators described by Reinart (2005) and in reference 29, respectively, thus allow the differentiation between infectious and non-infectious conditions. A possibility to establish the underlying local condition of a FUO by means of gene expression profiles was neither disclosed nor rendered obvious.

Thus, there is urgent need for possibilities for in vitro diagnosis of the underlying local inflammation in a fever of unknown origin. The availability of such in vitro methods will render the diagnosis of FUO quick and not as painful for the patient, allow for appropriate therapeutic measures, and significantly reduce the costs of the treatment.

The origin of the invention disclosed in the present patent application is the realization that gene activity profiles can be used to determine the underlying local inflammation of a FUO. The use of these gene activities is not possible with the clinical parameters conventionally used for diagnosis, however, it is very important for the initiation of a specialized therapy in intensive care.

Thus, it is the object of the present invention to use gene activity markers in order to make it possible to establish the local inflammation of a fever of unknown origin.

This object is solved by the features of claims 1, 14 and 33.

The present invention relates in particular to the use of gene expression profiles that have been obtained in vitro from a patient's sample for the establishment of the local inflammation of a fever of unknown origin.

A preferred embodiment of the present invention relates to the use of specific gene expression profiles which permit die localization of the underlying local inflammations. Examples for said local inflammations of a FUO are peritonitis, pneumonia, endocarditis or infections of the urinary tract.

The invention in particular relates to the gene expression profiles of at least 2 polynucleotides, selected from SEQ-IDs No 1 to 191, which are specific for peritonitis or pneumonia as local inflammations of a “fever of unknown origin”. Here, the gene activities of the polynucleotides with SEQ-IDs No 1 to 191 having similar expression activities can be pooled into diagnostic gene activity clusters.

These gene activity cluster are composed as follows:

Cluster 1: SEQ-ID No. 1 to SEQ-ID No. 77 peritonitis specific sequences with significant gene activity (table 3)

Cluster 2: SEQ-ID NO. 78 to SEQ-ID No. 191 pneumonia specific sequences with significant gene activity (table 3)

The invention furthermore comprises gene expression profiles of at least 2 polynucleotides, selected from SEQ-ID No. 192 to SEQ-ID No. 432, which are specific for a local inflammation, but not for peritonitis or pneumonia, of a “fever of unknown origin”.

Another embodiment of the invention also comprises gene expression profiles of at least 2 polynucleotides comprising 80% homology to SEQ-IDs No. 1 to SEQ-ID No. 432, for establishing the local inflammation of a fever of unknown origin.

The invention also includes the use of these gene expression profiles as inclusion or exclusion criterion to decide whether patients suffering from “fever of unknown origin” are included in clinical studies.

Another embodiment of the invention is the use of the gene expression profiles obtained in vitro for the creation of gene activity data for electronic further processing. These gene activity data can be used for the production of software for the description of the individual prognosis of a patient, for diagnosis purposes and/or patient data management systems.

Another use of the gene expression profiles obtained in vitro is the preparation of clinical expert systems and/or the modeling of cellular signal transduction pathways. Like modeling methods and/or programs are, for example. Ingenuity (Fa. Ingenuity Systems), Panther (Applied Biosystems) or other methods known to the person skilled in the art.

A preferred embodiment is characterized in that a specific gene and/or gene fragment is used for the generation of gene expression profiles, the gene and/or gene fragment being selected from a group consisting of SEQ-ID No. 1 to SEQ-ID No. 432 as well as gene fragments thereof with at least 20-2000 nucleotides.

A further embodiment of the invention is characterized in that the gene fragments comprise 20-200, preferably 20-80, nucleotides.

A further embodiment of the invention is characterized in that the gene expression profiles are determined by means of hybridization methods, in particular hybridization methods basing on micro arrays or real-time PGR. Hybridizing methods are well known to the person skilled in the art.

One further embodiment of the invention is a method, characterized in that for in vitro measurement of gene expression profiles and/or at least one gene activity cluster for establishing a local inflammation of a fever of unknown origin, characterized in that—in patients—the gene activity of a plurality of predetermined genes related to the source of infection are determined in a patient's sample.

Another embodiment of the invention is characterized in that for in vitro measurement of gene expression profiles and/or at least one gene activity cluster for establishing peritonitis or pneumonia as source of infection of a fever of unknown origin, in patients, the gene activity of a plurality of predetermined genes related to peritonitis and pneumonia as source of infection are determined in a patient's sample, wherein the genes and/or gene fragments specific for peritonitis and pneumonia of the local inflammation are selected from the group consisting of: SEQ-ID No. 1 to SEQ-ID No. 191 as well as gene fragments therefrom with at least 20-2000 nucleotides.

Another embodiment of the invention is characterized in that the specific sequences SEQ-ID No. 1 to SEQ-ID No. 191 are composed of the following diagnostic clusters:

-   Cluster 1: SEQ-ID No.1 to SEQ-ID No. 77 peritonitis specific     sequences with significant gene activity -   Cluster 2: SEQ-ID No. 78 to SEQ-ID No. 191 pneumonia specific     sequences with significant gene activity

A further embodiment of the invention is characterized in that the gene fragments comprise 20-200, preferably 20-80 nucleotides.

Another embodiment of the present invention is characterized in that at least 4 to 100 different genes and gene fragments are used.

Another embodiment of the present invention is characterized in that at least 200 different genes and/or gene fragments are used.

Another embodiment of the present invention is characterized in that at least 200 to 500 different genes and/or gene fragments are used.

Another embodiment of the present invention is characterized in that at least 500 to 1000 different genes and gene fragments are used.

Another embodiment of the present invention is characterized in that at least 1000 to 2000 different genes and gene fragments are used.

Another embodiment of the invention is characterized in that the genes or gene fragments listed in table 3 and table 4 and/or the sequences derived from their RNA are replaced by: synthetic analogues, aptamers. Spiegelmers as well as peptido- and morpholinonucleic acids.

Another embodiment of the invention is characterized in that the synthetic analogues of the genes comprise 20-100, in particular approx. 70 base pairs.

Another embodiment of the present invention is characterized in that the gene activity is determined by means of hybridization methods.

Another embodiment of the present invention is characterized in that the gene activity is determined by means of microarrays.

Another embodiment of the invention is characterized in that the gene activity is determined by hybridization-independent methods, in particular by enzymatic and/or chemical hydrolysis and/or amplification methods, preferably PGR, subsequent quantification of nucleic acids and/or of derivates and/or fragments thereof.

Another embodiment of the present invention is characterized in that the sample is selected from: tissue, body fluids, in particular blood, serum, plasma, urine, saliva or a mixture thereof.

Another embodiment of the present invention is characterized in that samples, in particular cell samples, are subjected to a lytic treatment, in order to release their cell contents.

In another embodiment of the invention, gene expression profiles that are obtained in vitro from a patient's sample and/or of probes used therefore, selected from the group consisting of SEQ-ID No. 1 to SEQ-ID No. 191 as well as gene fragments thereof with at least 20-2000 nucleotides are used for determining the gene activity or the protein products derived therefrom for the screening of active agents against fever of unknown origin and/or peritonitis and/or pneumonia and/or for the evaluation of the therapeutic effects of active agents against fever of unknown origin and/or peritonitis and/or pneumonia.

Another embodiment of the invention is characterized in that hybridizable synthetic analogues of the probes listed in tables 3 and 4 are used.

A further embodiment of the invention is characterized in that the gene fragments comprise 20-200, preferably 20-80 nucleotides.

The invention also relates to a kit containing a selection of sequences which are specific for the establishment of the local inflammation of a “fever of unknown origin”, and/or gene fragments thereof with at least 20-2000 nucleotides for the determination of gene expression profiles in vitro in a patient's sample, for determining of a source of infection and/or the source of infection of a fever of unknown origin.

Another embodiment of the invention is characterized in that the kit contains a selection of at least 2 polynucleotides with sequences according to SEQ-ID No. 1 to SEQ-ID No. 191 and/or gene fragments thereof with at least 20-2000 nucleotides for determining gene expression profiles in vitro in a patient's sample, for establishing peritonitis and/or pneumonia as local inflammation of a fever of unknown origin.

WORKING EXAMPLE

Test for the creation of gene expression profiles to establish the local inflammation of patients diagnosed with fever of unknown origin (1.3) and severe infection (30).

Measurement of the Differential Gene Expression

First of all, the differential gene expression between two groups of patients was tested, wherein the following was known from the groups:

i) the first (partially blinded) group were patients suffering from a severe infection [sepsis, classified according to 30] in the course of their intensive care treatment and diagnosed with “fever of unknown origin” (patient group 1). The local inflammation underlying the FUO was not known in these patients.

ii) the second group were patients who developed an acute generalized inflammation [SIRS, classified according to 30] with organ failure in the course of their treatment in intensive care, but in whom no infection was detected at any time during their treatment in intensive care (patient group 2).

Selected characteristics of both patient groups are shown in table 1. Information includes age, sex, as well as the SOFA-score as a measure for the function of the organ systems. In addition, the plasma protein levels of procalcitonine (PCT) and CRP as well as the number of leukocytes of the patients are given.

Reference samples were total RNA from SIG-M5 cell lines.

Each of the patients' samples was co-hybridized with the reference sample on one microarray each.

TABLE 1 Data of patient groups 1 and 2 patients with severe infection SIRS + OD patient group 1 patient group 2 Number of patients 39 37 Mortality 16 (41.0%) 2° (5.4%) Sex [m/f] 31/8 18/19 Age [years] 69 (11) 75 (14) SOFA Score 9 (2.5) 8* (2) Number of OD 3 (1) 2 (1) PCT [ng/ml] 2.44 (3.20) [36] 3.34 (4.13) [30] CRP [mg/l] 177 (124.4) [35] 91.6* (90.13) [36] WBC [no/l] 14400 (9050) 11900* (7400) *p < 0.05 (Wilcoxon rang sum test) °p = 0.003 (exact test of Fisher)

Median (IQR) Experimental Description: Drawing Blood and Isolation of RNA

At the time when “fever of unknown origin” was diagnosed, the whole blood of patient group 1 was drawn postoperatively from the patients by means of the PAXGene Kit according to the manufacturer's (Qiagen) instructions. The whole blood of patient group 2 was postoperatively drawn by means of the PAXGene Kit Kit according to the manufacturer's (Qiagen) instructions. After drawing whole blood, the total RNA of the samples was isolated using the PAXGene Blood RNA kit according to the manufacturer's (Qiagen) instructions.

Cell Cultivation

For cell cultivation (control samples) 19 cryo cell cultures (SIGM5) (frozen in liquid nitrogen) were used. The cells were each inoculated with 2 ml Iscove's medium (Biochrom AG) supplemented with 20% fetal calf serum (FCS). Subsequently, the cell cultures were incubated in 12 well plates for 24 hours at 37° C. in 5% CO2. Subsequently, the content of the 18 wells was parted in 2 parts with the same volume each, so that finally 3 plates of the same format (36 wells in total) were available. Afterwards, the cultivation was continued under the same conditions for 24 hours. Afterwards, the resulting cultures of 11 wells of each plate were combined and centrifuged (1000×g, 5 min, ambient temperature). The supernatant was removed and the cell pellet was dissolved in 40 ml of the above mentioned medium. These 40 ml of dissolved cells were distributed in equal shares in two 250 ml flasks and again incubated after adding 5 ml of the above-mentioned medium. 80 μl of the remaining 2 ml of the two remaining plates were placed in empty wells of the same plates that had previously been prepared with 1 ml of the above-mentioned medium. After 48 hours of incubation, only one of the 12 well plates was processed as follows: 500 μl were extracted from each well and combined. The resulting 6 ml were introduced into a 250 ml flask comprising approximately 10 ml of fresh medium. This mixture was centrifuged for 5 minutes with 1000×g at ambient temperature and dissolved in 10 ml of the above-mentioned medium. The following results were obtained by subsequent counting of cells: 1.5×107 cells per ml, 10 ml total volume, total number of cells: 1.5×108. As the number of cells was not yet sufficient, 2.5 ml of the above-mentioned cell suspension was introduced into 30 ml of the above-mentioned medium in a 250 ml (75 cm²) flask (4 flasks in total). After 72 hours of incubation 20 ml of fresh medium were added to each flask. After the subsequent incubation of 24 hours, the cells were counted as described above. The total amount of cells was 3.8×10⁸ cells. In order to obtain the desired number of cells of 2×106 cells, the cells were resuspended in 47.5 ml of the above mentioned medium in 4 flasks. After the incubation time of 24 hours, the cells were centrifuged and washed two times with phosphate buffer in absence of Ca²⁺ and Mg²⁺ (Biochrom AG).

The isolation of the total RNA is performed by means of NucleoSpin RNA L Kits (Machery&Nagel) according to the manufacturer's instructions. The above described process was repeated until the necessary number of cells was obtained. This was necessary to obtain the necessary amount of 6 mg total RNA corresponding to an efficiency of 600 μg RNA per 108 cells.

Reverse Transcription/Labeling/Hybridization

After drawing whole blood, the total RNA of the samples was isolated and tested for quality using the PAXGene Blood RNA kit (PreAnalytiX) according to the manufacturer's instructions. 10 μg total RNA were aliquoted from each sample and transcribed with 10 μg total RNA from SIGM5 cells as reference RNA to complementary DNA (cDNA) by means of the reverse transcriptase Superscript II (Invitrogen). Subsequently, the RNA was removed from the mixture by alkaline hydrolysis. In the reaction mixture a part of the dTTP was replaced by aminoallyl-dUTP (AA-dUTP) in order to render the linkage of the fluorescent dye to the cDNA possible at a later point of time.

After the purification of the reaction mixture, the cDNA of the samples and the controls were covalently labeled with the fluorescent dyes Alexa 647 and Alexa 555 and hybridized on a microarray of the SIRS-Lab company. On the microarray used, 5308 polynucleotides with lengths of 55 to 70 base pairs were immobilized. Each of the polynucleotides represents a human gene. Additionally there were control spots for quality assurance. One microarray is divided into 28 subarrays, each of the subarrays being arranged in a grid of 15×15 spots.

The hybridization and the subsequent washing and drying, respectively, were carried out according to the manufacturer's instructions for 10.5 hours at 42° C. using the hybridization station HS 400 (Tecan). The hybridization solution used was composed of the cDNA samples, each labelled, 3.5×SSC (1×SSC comprises 150 mM sodium chloride and 15 mM sodium citrate), 0.3% sodium lauryl sulfate (v/v) 25% formamide (v/v) and each 0.8 μg μl-l cot-1-DNA, yeast t-RNA and poly-A RNA. The subsequent washing of the microarrays was carried out at ambient temperature according to the following scheme: Rinse 90 seconds with washing buffer 1 (2×SSC, 0.03% sodium lauryl sulfate), with washing buffer 2 (1×SSC) and finally with washing buffer 3 (0.2×SSC). Subsequently, the microarrays were dried under a nitrogen flow at a pressure of 2.5 bar for more than 150 seconds at 30° C.

After hybridization, the hybridization signals of the microarrays were read by means of the GenePix 4000B (Axon) scanner and the expression ratios of the different expressed genes were determined by means of the GenePix Pro 4.0 (Axon) software.

Evaluation:

For the analysis, the average intensity of one spot was determined as median value of the corresponding spot pixel.

Correction of Systematic Errors:

Systematic errors were corrected according to the approach of Huber et al. [31]. According to this approach, the additive and the multiplicative bias in a microarray was estimated on the basis of 70% of the gene samples present. For all further computations, the signals were transformed by means of arcus sinus hyperbolicus.

For the analysis, the normalized and transformed relative ratios of the signals of the patients samples were calculated with respect to the general control. This means that the calculation for the gene no. j of the patient no. n revealed the data Gj,n=arcsinh (Scy5(j,n))−arcsinh(Scy3(j.n)), wherein [SCy3(j,n). SCy5(j,n)] is the associated signal pair. When a spot could not be analyzed for a patient (e.g. scanned picture is stained), the associated value was marked as “missing value”.

Statistical Comparison:

For comparison the paired random student test was employed per gene. Both random tests contained the values of the patient groups. In order to select the differentially expressed genes, the corresponding p-value was evaluated. It applied for the group of the selected genes that the associated p-value was smaller than 0.05.

In the sequence listing attached to the present application, the sequences indicated in tables 3 and 4 are individually allocated to one sequence ID (Sequence ID: 1 to Sequence ID: 432).

Thus, the gene activities ascertained and shown in tables 3 and 4 can be used for the distinction of infectious and non-infectious conditions. These results confirm the methods and results from the state of the art, as for example shown in (20-22).

Unblinding of Patient Group 1 and Correlation with the Ascertained Gene Activities of Table 3 and 4.

The unblinding of patient group 1 revealed that this patient group consisted of two subgroups:

1) Patients, in which FUO and a severe infection were diagnosed and the follow-up diagnosis identified peritonitis as underlying local infection (patient group 1a).

2) Patients, in which FUO and a severe infection were diagnosed and the follow-up diagnosis identified pneumonia as underlying local infection (patient group 1b).

Selected characteristics of the two patient groups 1a and 1b subsequent to the follow-up diagnosis are shown in table 2.

TABLE 2 Data of patient groups 1a and 1b Patient group 1a Patient group 1b Number of patients 15 24 Mortality 9 (60%) 7 (29.2%) Sex [m/f] 11/4 20/4 Age [years] 66 (9) 70 (13) SOFA Score 9 (2.5) 9 (2.25) Number of OD 3 (0) 2.5 (1) PCT [ng/ml] 6.05 (24.3) [13] 1.46* (1.98) [23] CRP [mg/l] 146 (87.5) 206 (95.75) [20] WBC [no/l] 14400 (11000) 14650 (6875) Local inflammation peritonitis pneumonia

In order to establish a local inflammation underlying a FUO in patients, the determined gene activities from table 3 and 4 were statistically classified according to significant gene activity clusters which showed a similar activity within patient groups 1a and 1b. In this context, it was surprisingly found out that, basing on all gene activities measured, a classification of gene activities into three cluster resulted:

Cluster 1: For peritonitis, a cluster of specific sequences with significant gene activity according to SEQ-ID No. 1 to SEQ-ID No. 77 was determined, which are part of the enclosed sequence listing.

Cluster 2: For pneumonia, a cluster of specific sequences with significant gene activity corresponding to SEQ-ID No. 78 to SEQ-ID No. 191 was determined, which are part of the enclosed sequence listing.

Cluster 3: Common set of sequences with similar significant gene activity in patients with severe infections which are specific for a local inflammation, but not for peritonitis or pneumonia of a “fever of unknown origin”, corresponding to SEQ-ID No. 192 to SEQ-ID No. 432, which are part of the enclosed sequence listing.

The three gene activity cluster are shown in table 3 (cluster 1 and 2) and 4 (cluster 3).

TABLE 3 Gene activity cluster 1 and 2 for establishing peritonitis (cluster 1) or pneumonia (cluster 2) as local inlammation of a FUO normalized and GenBank transformed expression signals Accession No. p value mean patient group 2 mean patient group 1a UniGene Cluster subgroup SeqID AA029887 0.0003 −0.145 0.174 1 Peritonitis 1 AA149226 0.0028 −0.248 0.298 Hs.494192 1 Peritonitis 2 AA398757 0.0000 −0.665 0.798 Hs.634201 1 Peritonitis 3 AA402274 0.0110 −0.216 0.259 Hs.567266 1 Peritonitis 4 AA419092 0.0046 0.152 −0.182 Hs.122575 1 Peritonitis 5 AA435854 0.0000 0.197 −0.236 1 Peritonitis 6 AA441793 0.0081 −0.159 0.191 Hs.132753 1 Peritonitis 7 AA458827 0.0002 −0.42 0.503 Hs.500546 1 Peritonitis 8 AA479285 0.0296 −0.094 0.113 Hs.536450 1 Peritonitis 9 AA490815 0.0073 0.144 −0.173 Hs.558393 1 Peritonitis 10 AA620762 0.0272 −0.14 0.168 Hs.371845 1 Peritonitis 11 AA629051 0.0017 0.13 −0.156 1 Peritonitis 12 AA693514 0.0224 0.09 −0.107 Hs.134229 1 Peritonitis 13 AA708806 0.0014 −0.129 0.154 Hs.596038 1 Peritonitis 14 AA731679 0.0415 −0.235 0.282 Hs.128619 1 Peritonitis 15 AI057616 0.0207 −0.102 0.123 Hs.83761 1 Peritonitis 16 AI086719 0.0347 0.105 −0.126 Hs.127657 1 Peritonitis 17 AI128170 0.0432 0.111 −0.133 Hs.592034 1 Peritonitis 18 AI150418 0.0353 0.111 −0.133 Hs.545647 1 Peritonitis 19 AI218498 0.0480 0.113 −0.135 Hs.585282 1 Peritonitis 20 AI221860 0.0304 −0.229 0.275 Hs.208353 1 Peritonitis 21 AI241294 0.0484 0.125 −0.15 Hs.308641 1 Peritonitis 22 AI282924 0.0001 −0.166 0.199 Hs.591290 1 Peritonitis 23 AI291041 0.0003 0.215 −0.258 1 Peritonitis 24 AI374599 0.0015 0.132 −0.158 Hs.128060 1 Peritonitis 25 AI418437 0.0066 −0.264 0.317 Hs.534383 1 Peritonitis 26 AI420865 0.0035 −0.148 0.178 Hs.541901 1 Peritonitis 27 AI499146 0.0126 −0.147 0.176 1 Peritonitis 28 AI520932 0.0211 −0.111 0.133 Hs.516707 1 Peritonitis 29 AI627453 0.0401 0.104 −0.125 Hs.370510 1 Peritonitis 30 AI634473 0.0158 0.107 −0.128 Hs.603284 1 Peritonitis 31 AI696984 0.0069 −0.121 0.145 Hs.262907 1 Peritonitis 32 AI732971 0.0169 0.179 −0.214 Hs.559775 1 Peritonitis 33 AI912592 0.0005 −0.148 0.177 Hs.86538 1 Peritonitis 34 BC004983 0.0486 −0.103 0.124 Hs.81328 1 Peritonitis 35 BC032713 0.0047 −0.131 0.157 Hs.87968 1 Peritonitis 36 CARD10 0.0003 −0.154 0.184 Hs.57973 1 Peritonitis 37 CCL15.2 0.0184 −0.096 0.115 Hs.272493 1 Peritonitis 38 CCL26 0.0259 0.127 −0.153 Hs.131342 1 Peritonitis 39 CCL27 0.0082 0.129 −0.154 Hs.459590 1 Peritonitis 40 CR1 0.0001 −0.167 0.2 Hs.334019 1 Peritonitis 41 DNAJB2 0.0000 −0.226 0.271 Hs.77768 1 Peritonitis 42 FADD 0.0004 −0.153 0.184 Hs.86131 1 Peritonitis 43 GH1.1 0.0033 −0.268 0.322 Hs.406754 1 Peritonitis 44 H05223 0.0000 −0.175 0.21 Hs.124638 1 Peritonitis 45 H11661 0.0000 −0.223 0.267 Hs.504091 1 Peritonitis 46 H91663 0.0009 −0.151 0.181 Hs.208052 1 Peritonitis 47 IF 0.0084 −0.158 0.19 Hs.312485 1 Peritonitis 48 IL21R 0.0065 −0.179 0.214 Hs.210546 1 Peritonitis 49 IL2RB 0.0223 0.341 −0.409 Hs.474787 1 Peritonitis 50 KBRAS2 0.0000 −0.204 0.244 Hs.632252 1 Peritonitis 51 MAP2K2 0.0000 −0.195 0.235 Hs.465627 1 Peritonitis 52 N64541 0.0088 0.172 −0.207 Hs.597199 1 Peritonitis 53 NM_004710 0.0388 −0.088 0.105 Hs.464210 1 Peritonitis 54 NM-001774 0.0002 −0.192 0.23 Hs.166556 1 Peritonitis 55 NM-002649 0.0001 −0.177 0.212 Hs.602240 1 Peritonitis 56 NM-006058 0.0018 −0.208 0.25 Hs.543850 1 Peritonitis 57 NM-006732 0.0046 −0.255 0.307 Hs.590958 1 Peritonitis 58 NM-014339 0.0019 −0.146 0.175 Hs.129751 1 Peritonitis 59 NM-139276 0.0008 −0.143 0.172 Hs.463059 1 Peritonitis 60 NOX2 0.0008 −0.154 0.184 Hs.292356 1 Peritonitis 61 PLAT.2 0.0116 −0.154 0.184 Hs.491582 1 Peritonitis 62 PPARD 0.0000 −0.179 0.215 Hs.485196 1 Peritonitis 63 R26118 0.0059 0.184 −0.22 Hs.594374 1 Peritonitis 64 R36650 0.0052 −0.126 0.151 Hs.591522 1 peritonitis 65 R43074 0.0480 0.08 −0.096 Hs.298851 1 Peritonitis 66 R53961 0.0118 −0.106 0.127 Hs.124128 1 Peritonitis 67 R96155 0.0026 0.131 −0.157 1 Peritonitis 68 TNFRSF6B.1 0.0045 −0.122 0.146 Hs.434878 1 Peritonitis 69 TRIAD3 0.0039 −0.143 0.172 Hs.487458 1 Peritonitis 70 TUCAN 0.0001 −0.153 0.183 Hs.446146 1 Peritonitis 71 W32272 0.0025 0.146 −0.176 Hs.594426 1 Peritonitis 72 W85706 0.0000 −0.214 0.257 Hs.458973 1 Peritonitis 73 XM-001687 0.0027 −0.155 0.186 Hs.77867 1 Peritonitis 74 XM-006800 0.0000 −0.235 0.282 Hs.591043 1 Peritonitis 75 XM-032902 0.0063 0.191 −0.23 Hs.593754 1 Peritonitis 76 XM-036966 0.0190 −0.097 0.116 Hs.431850 1 Peritonitis 77 GenBank Accession Nummer p value mean patient group 2 mean patient group 1b UniGene Cluster Subgroup SeqID AA017263 0.0099 0.16 −0.127 Hs.156727 2 Pneumonia 78 AA017301 0.0179 0.139 −0.11 Hs.85863 2 Pneumonia 79 AA031731 0.0015 −0.358 0.283 Hs.238964 2 Pneumonia 80 AA398760 0.0275 0.213 −0.168 Hs.570638 2 Pneumonia 81 AA400434 0.0088 0.137 −0.108 Hs.563200 2 Pneumonia 82 AA400470 0.0418 0.146 −0.115 Hs.97805 2 Pneumonia 83 AA402483 0.0138 0.169 −0.134 Hs.97313 2 Pneumonia 84 AA417980 0.0004 −0.281 0.223 Hs.479226 2 Pneumonia 85 AA428463 0.0195 −0.186 0.147 Hs.372739 2 Pneumonia 86 AA436250 0.0019 −0.361 0.286 Hs.490203 2 Pneumonia 87 AA452113 0.0054 0.144 −0.114 Hs.500643 2 Pneumonia 88 AA458912 0.0330 0.167 −0.132 Hs.281898 2 Pneumonia 89 AA459648 0.0086 0.154 −0.122 2 Pneumonia 90 AA478611 0.0132 −0.221 0.175 Hs.105616 2 Pneumonia 91 AA479727 0.0239 0.128 −0.101 Hs.23158 2 Pneumonia 92 AA514450 0.0107 0.141 −0.112 2 Pneumonia 93 AA541644 0.0000 −0.218 0.173 Hs.232165 2 Pneumonia 94 AA548307 0.0234 0.137 −0.108 Hs.399800 2 Pneumonia 95 AA626313 0.0137 0.142 −0.113 Hs.116150 2 Pneumonia 96 AA628539 0.0280 −0.132 0.105 Hs.371001 2 Pneumonia 97 AA699706 0.0043 −0.268 0.212 Hs.464779 2 Pneumonia 98 AA844053 0.0402 0.119 −0.094 Hs.535257 2 Pneumonia 99 AA887470 0.0423 −0.12 0.095 Hs.531081 2 Pneumonia 100 AA897543 0.0122 0.235 −0.186 Hs.148217 2 Pneumonia 101 AA906116 0.0083 0.264 −0.209 Hs.521545 2 Pneumonia 102 AA910923 0.0030 0.194 −0.153 Hs.191164 2 Pneumonia 103 AA935135 0.0222 0.148 −0.117 Hs.585129 2 Pneumonia 104 AA969039 0.0051 0.152 −0.121 Hs.544636 2 Pneumonia 105 AA992540 0.0002 0.258 −0.204 Hs.491869 2 Pneumonia 106 ADRA2A 0.0391 −0.116 0.092 Hs.249159 2 Pneumonia 107 AF077011 0.0003 0.17 −0.135 Hs.459095 2 Pneumonia 108 AI005466 0.0005 0.175 −0.139 Hs.602706 2 Pneumonia 109 AI023336 0.0002 0.217 −0.172 Hs.370267 2 Pneumonia 110 AI140065 0.0091 −0.25 0.198 Hs.146594 2 Pneumonia 111 AI142427 0.0101 −0.219 0.174 Hs.300684 2 Pneumonia 112 AI150305 0.0231 0.202 −0.16 Hs.128031 2 Pneumonia 113 AI160757 0.0119 0.225 −0.178 Hs.408960 2 Pneumonia 114 AI191762 0.0381 0.206 −0.163 Hs.495918 2 Pneumonia 115 AI264774 0.0041 0.17 −0.135 Hs.514242 2 Pneumonia 116 AI272798 0.0478 −0.103 0.082 Hs.479808 2 Pneumonia 117 AI285411 0.0306 −0.142 0.113 Hs.635265 2 Pneumonia 118 AI375046 0.0005 0.238 −0.189 2 Pneumonia 119 AI421397 0.0391 −0.117 0.093 Hs.507025 2 Pneumonia 120 AI492528 0.0268 −0.158 0.125 2 Pneumonia 121 AI554942 0.0448 0.228 −0.181 Hs.570675 2 Pneumonia 122 AI568793 0.0058 −0.322 0.255 Hs.368944 2 Pneumonia 123 AI625724 0.0046 −0.225 0.178 Hs.185597 2 Pneumonia 124 AI635650 0.0212 0.131 −0.104 2 Pneumonia 125 AI654928 0.0000 0.272 −0.216 Hs.196133 2 Pneumonia 126 AI685048 0.0004 −0.165 0.131 Hs.369785 2 Pneumonia 127 AI700169 0.0010 −0.334 0.264 Hs.584910 2 Pneumonia 128 AI745409 0.0032 −0.265 0.21 Hs.204924 2 Pneumonia 129 AI798514 0.0314 0.143 −0.113 Hs.632218 2 Pneumonia 130 AI799683 0.0047 −0.149 0.118 Hs.592083 2 Pneumonia 131 AI799767 0.0323 0.22 −0.175 Hs.209226 2 Pneumonia 132 AI801504 0.0108 −0.135 0.107 Hs.16064 2 Pneumonia 133 AI808903 0.0240 −0.15 0.118 Hs.519855 2 Pneumonia 134 AI811774 0.0115 −0.148 0.117 2 Pneumonia 135 AI861979 0.0148 0.143 −0.114 Hs.469134 2 Pneumonia 136 AI866656 0.0007 0.164 −0.13 Hs.211814 2 Pneumonia 137 BC001604 0.0001 −0.214 0.169 Hs.182014 2 Pneumonia 138 C2 0.0016 0.165 −0.13 Hs.408903 2 Pneumonia 139 H02254 0.0280 0.245 −0.194 Hs.632489 2 Pneumonia 140 H05436 0.0000 0.241 −0.191 Hs.11110 2 Pneumonia 141 H11068 0.0045 −0.174 0.138 Hs.317243 2 Pneumonia 142 H22946 0.0015 0.171 −0.135 Hs.534590 2 Pneumonia 143 H38159 0.0026 0.211 −0.167 Hs.162996 2 Pneumonia 144 H50201 0.0430 −0.17 0.135 Hs.21413 2 Pneumonia 145 H73724 0.0002 0.211 −0.167 Hs.119882 2 Pneumonia 146 H83996 0.0020 0.147 −0.116 Hs.153458 2 Pneumonia 147 ICAM4 0.0113 0.118 −0.093 Hs.631609 2 Pneumonia 148 IL18mRNA 0.0001 −0.182 0.144 Hs.83077 2 Pneumonia 149 IL26mRNA 0.0293 0.108 −0.085 Hs.272350 2 Pneumonia 150 LTBP4 0.0499 −0.161 0.128 Hs.466766 2 Pneumonia 151 LTBR 0.0191 −0.164 0.13 Hs.1116 2 Pneumonia 152 M37435 0.0488 −0.109 0.087 Hs.173894 2 Pneumonia 153 MAP4K4 0.0192 −0.13 0.103 Hs.431550 2 Pneumonia 154 MAPK11.1 0.0268 0.116 −0.092 Hs.57732 2 Pneumonia 155 MAPK7 0.0195 −0.233 0.184 Hs.150136 2 Pneumonia 156 N29761 0.0156 0.552 −0.437 Hs.9315 2 Pneumonia 157 N49848 0.0384 0.213 −0.168 Hs.104091 2 Pneumonia 158 N55249 0.0426 −0.185 0.147 Hs.143347 2 Pneumonia 159 N64649 0.0181 0.166 −0.131 Hs.102402 2 Pneumonia 160 N69363 0.0284 0.158 −0.125 Hs.594444 2 Pneumonia 161 N70546 0.0071 −0.253 0.2 Hs.155040 2 Pneumonia 162 N80868 0.0128 0.143 −0.113 Hs.211426 2 Pneumonia 163 NFKBIL2 0.0003 −0.184 0.146 Hs.459376 2 Pneumonia 164 NM-001295 0.0001 −0.189 0.149 Hs.301921 2 Pneumonia 165 NM-057158 0.0214 0.169 −0.134 Hs.417962 2 Pneumonia 166 NOX1.2 0.0265 0.239 −0.189 Hs.592227 2 Pneumonia 167 R00206 0.0028 0.199 −0.158 Hs.533551 2 Pneumonia 168 R09463 0.0145 0.176 −0.139 Hs.344165 2 Pneumonia 169 R16722 0.0334 0.221 −0.175 Hs.124246 2 Pneumonia 170 R41771 0.0013 0.153 −0.121 Hs.591601 2 Pneumonia 171 R42593 0.0207 0.154 −0.122 Hs.80395 2 Pneumonia 172 R42778 0.0077 0.215 −0.17 Hs.553877 2 Pneumonia 173 R43910 0.0009 0.398 −0.315 Hs.586760 2 Pneumonia 174 R46801 0.0070 −0.172 0.136 Hs.343664 2 Pneumonia 175 R49244 0.0078 0.125 −0.099 Hs.443258 2 Pneumonia 176 R50755 0.0000 0.192 −0.152 Hs.633191 2 Pneumonia 177 R60898 0.0032 0.136 −0.108 Hs.568242 2 Pneumonia 178 R62926 0.0257 0.169 −0.134 Hs.285193 2 Pneumonia 179 R79239 0.0087 0.18 −0.143 Hs.530588 2 Pneumonia 180 R80259 0.0020 0.16 −0.126 Hs.595477 2 Pneumonia 181 TGFB1 0.0136 −0.122 0.097 Hs.155218 2 Pneumonia 182 W88496 0.0318 0.214 −0.17 Hs.314413 2 Pneumonia 183 X57817 0.0119 −0.639 0.506 Hs.561078 2 Pneumonia 184 XM-006953 0.0341 0.208 −0.165 Hs.355307 2 Pneumonia 185 XM-028642 0.0149 −0.175 0.139 Hs.505654 2 Pneumonia 186 XM-033972 0.0496 −0.121 0.096 Hs.492740 2 Pneumonia 187 XM-034166 0.0028 0.149 −0.118 Hs.462525 2 Pneumonia 188 XM-041844 0.0194 0.159 −0.126 Hs.36 2 Pneumonia 189 XM-049849 0.0006 0.219 −0.174 Hs.512898 2 Pneumonia 190 XM-057131 0.0000 −0.313 0.248 Hs.525157 2 Pneumonia 191

TABLE 4 Common set of sequences with similar significant gene activity in patients with severe infections which are specific for a local inflammation, but not for peritonitis or pneumonia of a “fever of unknown origin”. normalized and transformed GenBank expression signals Accession p value p value mean patient mean patient mean patient Nummer (patient group 1a) (patient group 1b) group 2 group 1a group 1b UniGene Cluster SeqID AA035428 0.006 0.007 0.15 −0.17 −0.15 Hs.437006 3 192 AA044390 0.015 0 −0.22 0.27 0.27 Hs.516217 3 193 AA046302 0.032 0 0.15 −0.17 −0.35 Hs.21611 3 194 AA059314 0.037 0.011 0.15 −0.18 −0.22 Hs.433445 3 195 AA151104 0.001 0 0.24 −0.29 −0.29 Hs.73454 3 196 AA397913 0.006 0.04 −0.12 0.14 0.11 Hs.549040 3 197 AA398331 0.018 0.007 0.16 −0.19 −0.2 Hs.599407 3 198 AA400790 0.011 0.006 0.22 −0.26 −0.24 Hs.127999 3 199 AA418841 0.039 0.03 −0.16 0.19 0.13 Hs.475319 3 200 AA425808 0 0.005 0.22 −0.27 −0.14 3 201 AA426618 0.008 0.007 0.16 −0.19 −0.15 Hs.585398 3 202 AA455638 0.045 0.007 −0.14 0.17 0.19 Hs.444332 3 203 AA461499 0.029 0.014 0.14 −0.16 −0.15 Hs.99546 3 204 AA478985 0.012 0.008 0.17 −0.2 −0.15 Hs.279784 3 205 AA514237 0 0.001 −0.23 0.28 0.19 Hs.147880 3 206 AA620760 0.007 0.016 0.21 −0.25 −0.21 Hs.633241 3 207 AA682790 0.002 0.04 0.16 −0.19 −0.11 3 208 AA702492 0 0.002 −0.29 0.35 0.17 Hs.368563 3 209 AA703200 0.01 0.001 0.17 −0.2 −0.18 Hs.597767 3 210 AA740907 0.004 0 0.15 −0.18 −0.27 Hs.88297 3 211 AA759092 0.016 0.025 0.11 −0.14 −0.15 Hs.121439 3 212 AA781411 0.005 0.021 0.16 −0.2 −0.12 Hs.166015 3 213 AA807376 0.009 0.015 0.14 −0.17 −0.17 Hs.370414 3 214 AA813145 0.018 0 0.16 −0.19 −0.38 Hs.601872 3 215 AA845015 0.041 0.02 0.12 −0.15 −0.13 Hs.631866 3 216 AA845475 0 0.022 −0.2 0.24 0.1 Hs.487393 3 217 AA860398 0.014 0.018 0.12 −0.14 −0.15 Hs.569748 3 218 AA894523 0.013 0 0.13 −0.15 −0.18 Hs.10734 3 219 AA947111 0.004 0.006 0.13 −0.15 −0.11 Hs.562136 3 220 ADRB1 0 0 −0.2 0.24 0.25 Mm.46797 3 221 AHSG 0.022 0.02 0.22 −0.26 −0.18 Hs.324746 3 222 AI023558 0.001 0.001 0.15 −0.18 −0.17 Hs.131417 3 223 AI041544 0 0 −0.22 0.26 0.16 Hs.575480 3 224 AI091867 0 0 −0.22 0.26 0.24 Hs.631761 3 225 AI093704 0.009 0.012 −0.18 0.21 0.19 Hs.603146 3 226 AI097494 0.002 0.005 0.17 −0.21 −0.16 Hs.307984 3 227 AI148246 0.024 0.004 0.14 −0.17 −0.18 Hs.474251 3 228 AI167874 0.006 0.002 0.13 −0.15 −0.16 Hs.71023 3 229 AI203091 0.016 0.027 0.13 −0.15 −0.12 Hs.604090 3 230 AI203697 0.001 0.016 −0.15 0.18 0.09 Hs.567342 3 231 AI220662 0.049 0.019 −0.12 0.15 0.1 Hs.508720 3 232 AI222359 0.005 0.003 0.23 −0.28 −0.29 Hs.556230 3 233 AI223092 0.004 0.015 0.16 −0.19 −0.18 Hs.147880 3 234 AI264626 0.001 0.005 0.16 −0.19 −0.12 3 235 AI267659 0.026 0.031 0.13 −0.15 −0.11 3 236 AI271764 0 0.003 −0.31 0.37 0.28 Hs.446357 3 237 AI342905 0.032 0.04 0.15 −0.18 −0.17 Hs.604613 3 238 AI357099 0.005 0.025 0.28 −0.34 −0.26 Hs.584910 3 239 AI373295 0.012 0.034 0.15 −0.18 −0.13 Hs.544825 3 240 AI373525 0.018 0.001 0.11 −0.13 −0.14 Hs.539391 3 241 AI378275 0.006 0.018 0.18 −0.21 −0.15 Hs.61271 3 242 AI453476 0.02 0.031 0.15 −0.18 −0.14 Hs.168677 3 243 AI478776 0.001 0.042 −0.18 0.22 0.15 3 244 AI539271 0.027 0.016 0.19 −0.23 −0.23 Hs.478000 3 245 AI554283 0.043 0.021 0.14 −0.17 −0.16 Hs.420529 3 246 AI565469 0.015 0 0.16 −0.19 −0.22 Hs.638685 3 247 AI582909 0 0 0.2 −0.24 −0.22 Hs.578450 3 248 AI589096 0.002 0.036 −0.23 0.27 0.18 Hs.638946 3 249 AI590144 0.003 0.022 0.27 −0.33 −0.24 Hs.508848 3 250 AI613038 0.012 0 −0.15 0.17 0.26 3 251 AI627286 0.008 0.003 0.12 −0.14 −0.14 Hs.191073 3 252 AI628322 0.006 0.038 0.22 −0.27 −0.12 Hs.530538 3 253 AI652609 0.027 0.012 0.12 −0.14 −0.12 Hs.567425 3 254 AI692869 0.002 0.028 0.24 −0.28 −0.19 Hs.202419 3 255 AI696291 0.027 0.033 0.21 −0.25 −0.25 Hs.528671 3 256 AI700444 0.029 0.019 0.18 −0.21 −0.23 Hs.564343 3 257 AI733177 0 0.004 −0.22 0.27 0.22 Hs.421340 3 258 AI733269 0 0.003 −0.26 0.31 0.18 Hs.418045 3 259 AI733498 0.045 0.001 0.16 −0.19 −0.32 Hs.573606 3 260 AI738831 0 0.032 0.26 −0.32 −0.14 Hs.268606 3 261 AI739381 0.005 0.004 0.14 −0.16 −0.2 Hs.512763 3 262 AI742529 0 0.003 −0.22 0.27 0.16 Hs.591095 3 263 AI799137 0.048 0.006 −0.16 0.19 0.27 Hs.432690 3 264 AI808410 0.006 0.008 −0.16 0.19 0.15 Hs.233955 3 265 AI859370 0.027 0.015 0.12 −0.14 −0.14 Hs.607181 3 266 AI859777 0.013 0.011 0.22 −0.26 −0.25 Hs.301819 3 267 AI860121 0.001 0.004 −0.21 0.25 0.23 Hs.501684 3 268 AI889310 0 0 −0.21 0.25 0.17 Hs.511903 3 269 AI890962 0.026 0.017 0.13 −0.16 −0.12 Hs.25601 3 270 AI913322 0.009 0.023 −0.24 0.29 0.19 Hs.107740 3 271 AI924028 0.003 0.003 0.28 −0.34 −0.27 Hs.326391 3 272 AI924296 0.017 0.041 0.11 −0.13 −0.11 Hs.487479 3 273 AI925451 0.046 0.008 0.16 −0.19 −0.18 Hs.629605 3 274 AI926659 0.001 0.04 −0.23 0.27 0.15 Hs.363558 3 275 AI933607 0 0.002 −0.25 0.31 0.17 Hs.632296 3 276 AI936462 0.016 0.012 −0.13 0.16 0.11 3 277 ARHA 0.001 0.004 −0.18 0.22 0.13 Hs.247077 3 278 ASC 0.001 0.014 −0.2 0.24 0.11 Hs.499094 3 279 B3GALT3 0.005 0.01 0.21 −0.25 −0.18 Hs.418062 3 280 BC013302 0.003 0.033 −0.13 0.16 0.08 Hs.437594 3 281 BC021289 0.023 0.005 −0.27 0.33 0.27 Hs.75431 3 282 BC024270 0 0.017 −0.15 0.18 0.13 Hs.136164 3 283 BCL6 0.003 0.011 −0.26 0.32 0.21 Hs.636990 3 284 BZRP 0 0 −0.47 0.56 0.37 Hs.202 3 285 BZRP.1 0.002 0 −0.34 0.41 0.35 Hs.202 3 286 C1QBP 0 0.001 −0.24 0.28 0.23 Hs.622699 3 287 C1S 0.015 0.037 0.12 −0.15 −0.09 Hs.458355 3 288 C8B 0.005 0 0.13 −0.16 −0.2 Hs.391835 3 289 C9 0 0.001 −0.25 0.3 0.15 Hs.481980 3 290 CCR7 0.037 0.024 0.11 −0.13 −0.12 Hs.370036 3 291 CD59 0.007 0.015 −0.2 0.24 0.17 Hs.633297 3 292 CDKN1A 0.049 0.007 −0.12 0.14 0.18 Hs.370771 3 293 CKM 0.004 0.003 0.2 −0.24 −0.22 Hs.334347 3 294 EDARADD 0 0 −0.24 0.29 0.2 Hs.352224 3 295 EPB41 0.018 0.013 0.2 −0.25 −0.25 Hs.175437 3 296 FADD 0 0.009 −0.21 0.25 0.12 Hs.86131 3 297 FLOT2 0 0 −0.35 0.42 0.29 Hs.514038 3 298 G3BP2 0.001 0.003 −0.19 0.23 0.22 Hs.593867 3 299 GADD45A 0.001 0.007 −0.27 0.33 0.21 Hs.80409 3 300 H16716 0.002 0 −0.25 0.31 0.25 Hs.448889 3 301 H18435 0.012 0.001 0.18 −0.22 −0.31 3 302 H18649 0 0.007 0.29 −0.34 −0.19 3 303 H23819 0.015 0.004 0.17 −0.2 −0.22 Hs.59093 3 304 H30516 0.012 0.031 0.17 −0.2 −0.14 Hs.482411 3 305 H44908 0 0 −0.28 0.34 0.23 Hs.591171 3 306 H61449 0.009 0 0.13 −0.15 −0.18 Hs.528368 3 307 H98244 0.001 0.019 0.23 −0.28 −0.17 Hs.143707 3 308 H99099 0.003 0.029 −0.22 0.26 0.17 Hs.205742 3 309 HSPA1A 0.011 0.019 −0.16 0.19 0.13 Hs.520028 3 310 HSPA8.1 0.005 0.006 −0.2 0.23 0.23 Hs.180414 3 311 HSPB1 0 0.013 −0.41 0.5 0.14 Hs.520973 3 312 ICAM5 0.003 0.003 −0.13 0.15 0.13 Hs.465862 3 313 IFNA5 0.012 0 −0.16 0.19 0.21 Hs.37113 3 314 IKBKG 0.001 0 −0.13 0.16 0.14 Hs.43505 3 315 IL10RB 0 0.004 −0.23 0.28 0.17 Hs.512211 3 316 IL12B 0.036 0.015 0.32 −0.39 −0.28 Hs.674 3 317 IL1RN 0.002 0 −0.31 0.37 0.27 Hs.594611 3 318 IL2RG 0 0.013 −0.24 0.29 0.12 Hs.84 3 319 IL6R 0.002 0.001 −0.16 0.19 0.19 Hs.591492 3 320 IL7R 0.019 0.04 0.21 −0.26 −0.17 Hs.591742 3 321 M37435 0.013 0.017 −0.13 0.15 0.13 Hs.173894 3 322 M61199 0.003 0.028 −0.22 0.26 0.16 Hs.591602 3 323 MAP3K11 0.024 0.01 −0.14 0.16 0.13 Hs.502872 3 324 MAP3K6 0.032 0.041 −0.12 0.15 0.11 Hs.194694 3 325 MAPK14 0 0.004 −0.24 0.28 0.19 Hs.588289 3 326 MAPK14.3 0 0.001 −0.26 0.31 0.25 Hs.588289 3 327 MAPK8.3 0.025 0.016 0.11 −0.13 −0.14 Hs.138211 3 328 MYD88 0 0 −0.25 0.3 0.25 Hs.82116 3 329 MYL2 0.032 0 −0.17 0.2 0.23 Hs.491359 3 330 N32857 0.004 0.02 −0.54 0.65 0.45 Hs.491767 3 331 N51537 0.042 0.002 0.15 −0.18 −0.19 Hs.525485 3 332 N52915 0.005 0 0.16 −0.19 −0.18 3 333 N53973 0.014 0.006 0.13 −0.16 −0.15 Hs.585782 3 334 N67859 0.004 0.041 −0.16 0.19 0.12 Hs.125829 3 335 NET1 0.021 0.013 −0.11 0.13 0.13 Hs.610771 3 336 NM_001540 0 0.013 −0.2 0.24 0.13 Hs.626419 3 337 NM_003258 0.005 0 −0.21 0.25 0.27 Hs.515122 3 338 NM_006936 0.001 0.001 −0.25 0.3 0.2 Hs.474005 3 339 NM_016184 0.017 0.022 0.22 −0.27 −0.24 Hs.504657 3 340 NM_025139 0.014 0.003 0.19 −0.23 −0.29 Hs.471610 3 341 NM_031311 0 0.024 0.5 −0.6 −0.24 Hs.233389 3 342 NM-000061 0.005 0.047 −0.15 0.18 0.1 Hs.159494 3 343 NM-000584 0.017 0.007 −0.18 0.21 0.21 Hs.632880 3 344 NM-000760 0.002 0.011 −0.18 0.21 0.13 Hs.524517 3 345 NM-001013 0.015 0.027 −0.11 0.13 0.11 Hs.546288 3 346 NM-001101 0 0 −0.27 0.33 0.19 Hs.593869 3 347 NM-001288 0.007 0.001 −0.14 0.17 0.18 Mm.388801 3 348 NM-001315 0 0.001 −0.25 0.3 0.22 Hs.588289 3 349 NM-001569 0.001 0.012 −0.16 0.19 0.11 Hs.522819 3 350 NM-001765 0.041 0.005 −0.12 0.14 0.16 Hs.1311 3 351 NM-001772 0.018 0.004 −0.12 0.14 0.12 Hs.83731 3 352 NM-002128 0.009 0.044 −0.2 0.24 0.15 Hs.593339 3 353 NM-002394 0 0.012 −0.19 0.23 0.12 Hs.502769 3 354 NM-002401 0.037 0.003 −0.14 0.17 0.17 Hs.29282 3 355 NM-002415 0 0.025 −0.24 0.28 0.14 Hs.632781 3 356 NM-002953 0 0 −0.19 0.23 0.21 Hs.149957 3 357 NM-003153 0 0.041 −0.2 0.24 0.13 Hs.524518 3 358 NM-003268 0 0.005 −0.31 0.38 0.45 Hs.135853 3 359 NM-003684 0.017 0.001 −0.17 0.2 0.16 Hs.371594 3 360 NM-004257 0 0 −0.25 0.3 0.19 Hs.446350 3 361 NM-004635 0.02 0.031 −0.1 0.12 0.11 Hs.624942 3 362 NM-004740 0 0.001 −0.25 0.3 0.19 Hs.462590 3 363 NM-005620 0.001 0.001 −0.23 0.27 0.22 Hs.547382 3 364 NM-005803 0.002 0.001 −0.15 0.18 0.15 Hs.179986 3 365 NM-007328 0.005 0 0.36 −0.43 −0.38 Hs.512576 3 366 NM-018643 0 0.035 0.39 −0.47 −0.14 Hs.283022 3 367 NM-138556 0.03 0.009 0.17 −0.2 −0.1 Hs.174312 3 368 PPGB 0 0.015 −0.22 0.26 0.14 Hs.609336 3 369 PPP4C 0 0 −0.19 0.23 0.15 Hs.534338 3 370 PRP4.1 0.035 0.005 −0.2 0.24 0.24 Mm.10027 3 371 R00742 0.007 0.037 0.16 −0.19 −0.15 Hs.275675 3 372 R05804 0.034 0.02 0.12 −0.15 −0.14 Hs.348308 3 373 R26635 0 0.041 −0.49 0.59 0.16 Hs.178499 3 374 R37251 0.033 0.038 −0.16 0.19 0.17 Hs.479099 3 375 R39782 0 0.002 0.22 −0.26 −0.2 Hs.21145 3 376 R40406 0.022 0.035 −0.14 0.16 0.2 Hs.2853 3 377 R42461 0.004 0.008 −0.2 0.23 0.26 Hs.579115 3 378 R42782 0.026 0.017 −0.17 0.21 0.14 Hs.434971 3 379 R43203 0.011 0.027 0.3 −0.36 −0.25 Hs.73828 3 380 R43722 0.033 0.032 −0.2 0.23 0.21 3 381 R45159 0 0 0.23 −0.28 −0.22 Hs.271285 3 382 R45355 0 0 −0.18 0.21 0.2 Hs.201805 3 383 R52949 0.024 0.035 0.16 −0.19 −0.17 Hs.622398 3 384 R54442 0.001 0.006 0.24 −0.28 −0.23 Hs.416139 3 385 R56890 0.011 0.002 0.14 −0.16 −0.14 Hs.592205 3 386 R58974 0.033 0.034 0.13 −0.16 −0.2 Hs.335205 3 387 R84393 0.027 0.023 0.15 −0.17 −0.11 Hs.387255 3 388 R89802 0.006 0 0.18 −0.22 −0.17 Hs.93670 3 389 RAC1 0.01 0.01 −0.11 0.13 0.14 Hs.413812 3 390 RAC3 0 0 −0.35 0.41 0.26 Hs.45002 3 391 SERCA2-2 0 0.004 −0.17 0.2 0.15 Hs.633656 3 392 SPTLC2 0 0.007 −0.19 0.23 0.2 Hs.435661 3 393 T65410 0.018 0.042 −0.2 0.24 0.19 Hs.125116 3 394 T90460 0.005 0.023 −0.15 0.18 0.12 Hs.102471 3 395 T91086 0.044 0.015 0.2 −0.24 −0.21 3 396 T91795 0.038 0.041 0.14 −0.17 −0.16 Hs.502872 3 397 T95815 0.038 0.032 0.09 −0.11 −0.12 Hs.336994 3 398 TNFSF14 0.004 0.001 0.13 −0.16 −0.17 Hs.129708 3 399 TNFSF9 0.001 0.03 −0.19 0.22 0.14 Hs.1524 3 400 TRAF3 0.014 0.041 −0.15 0.18 0.11 Hs.510528 3 401 U07802 0.004 0.023 0.24 −0.28 −0.26 Hs.503093 3 402 UGCG 0.009 0 −0.26 0.31 0.53 Hs.304249 3 403 W86767 0.046 0.001 0.1 −0.12 −0.17 Hs.632594 3 404 X05875 0.011 0.021 −0.37 0.45 0.23 Hs.99863 3 405 X64641 0.004 0.015 −0.46 0.56 0.44 Hs.449621 3 406 XM-003937 0.002 0.001 0.26 −0.32 −0.38 Hs.591258 3 407 XM-004256 0.014 0 −0.31 0.38 0.6 Hs.606320 3 408 XM-006867 0.002 0.001 −0.19 0.22 0.19 Hs.591014 3 409 XM-007417 0.031 0.016 0.1 −0.12 −0.27 Hs.636674 3 410 XM-008679 0.009 0.019 −0.28 0.33 0.24 Hs.408312 3 411 XM-009475 0.001 0.001 −0.36 0.44 0.4 Hs.388004 3 412 XM-012039 0 0.004 −0.28 0.33 0.24 Hs.568921 3 413 XM-015278 0 0.001 −0.19 0.23 0.21 Hs.334019 3 414 XM-015396 0 0 −0.41 0.49 0.35 Hs.507658 3 415 XM-015815 0.008 0.007 −0.23 0.27 0.25 Hs.509067 3 416 XM-027358 0 0.042 −0.29 0.35 0.16 Hs.592992 3 417 XM-030326 0.002 0.021 −0.22 0.26 0.17 Hs.626357 3 418 XM-030906 0 0 −0.23 0.27 0.22 Hs.155218 3 419 XM-031242 0 0 −0.25 0.3 0.29 Hs.527778 3 420 XM-033862 0.004 0.001 −0.13 0.15 0.14 Hs.181128 3 421 XM-038024 0.024 0.033 0.14 −0.17 −0.11 Hs.318547 3 422 XM-041101 0.004 0 −0.19 0.22 0.18 Hs.504877 3 423 XM-042066 0.006 0.025 −0.14 0.17 0.15 Hs.508461 3 424 XM-046575 0.028 0.007 0.18 −0.21 −0.2 Hs.562457 3 425 XM-047570 0 0 −0.26 0.32 0.21 Hs.495912 3 426 XM-048068 0.001 0 −0.24 0.29 0.23 Hs.531668 3 427 XM-052636 0 0 −0.27 0.32 0.23 Hs.634911 3 428 XM-055188 0.029 0.011 −0.17 0.2 0.18 Hs.76753 3 429 XM-056556 0 0.019 −0.34 0.41 0.17 Hs.501497 3 430 XM-057356 0 0.009 −0.22 0.26 0.23 Hs.268675 3 431 XM-114018 0.001 0.012 −0.17 0.21 0.12 Hs.591382 3 432

Thus, the specific gene activity cluster 1 and 2 ascertained are usable for the invention for establishing peritonitis or pneumonia as local inflammation for “fever of unknown origin”.

The gene activity cluster 3 is usable for the invention for establishing a local inflammation of a FUO which is not peritonitis or pneumonia.

REFERENCES

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1.-15. (canceled)
 16. Use of gene expression profiles obtained in vitro from a patient's sample for establishing a local inflammation of a fever of unknown origin (FUO), wherein polynucleotides used for establishing said gene expression profiles show similar gene activity data in their expression behaviour and are grouped in diagnostic gene activity clusters and wherein the diagnostic gene activity clusters are composed as follows: Cluster 1: SEQ-ID No.1 to SEQ-ID No. 77 Cluster 2: SEQ-ID No. 78 to SEQ-ID No. 191 Cluster 3: SEQ-ID No. 192 to SEQ-ID No.
 432. 17. The use according to claim 1, wherein the polynucleotides of SEQ-IDs 1 to 77 are specific for peritonitis as the local inflammation of a FUO, the polynucleotides of SEQ-IDs 78 to SEQ-ID No. 191 are specific for pneumonia as the local inflammation of a FUO, and the polynucleotides of SEQ-IDs 192 to 432 are specific for the local inflammation of a FUO but not for peritonitis or pneumonia as the local inflammation of a FUO.
 18. The use according to claim 1, wherein the gene expression profiles of at least 2 polynucleotides are recorded.
 19. The use according to claim 1, wherein the gene expression profiles are utilized as inclusion or exclusion criterion to decide whether patients with the FUO are included into clinical studies or excluded therefrom and to establish gene activity data for electronic further processing.
 20. The use according to claim 1, wherein the gene activity data obtained are used for the production of software for the description of the individual prognosis of a patient, for diagnostic purposes and/or patent data management systems, and/or the gene expression profiles obtained in vitro from a patient's sample are used for the creation of clinical expert systems and/or for modelling cellular signal transduction pathways.
 21. The use according to claim 1, wherein a specific gene or gene fragment is used for generation of the gene expression profile, the gene or gene fragment being selected from the group consisting of SEQ-ID No. 1 to SEQ-ID No. 432, gene fragments thereof with at least 20-2000 nucleotides and genes with a homology of sequence of at least 80%.
 22. The use according to claim 1, wherein the gene expression profiles are ascertained by means of hybridizing methods, in particular hybridizing methods based on microarrays or real-time PCR.
 23. A method for in vitro measurement of gene expression profiles and at least one gene activity cluster for establishing a local inflammation of a FUO, characterized in that, in a patient, the gene activity of a plurality of certain genes related to the local inflammation of a FUO is determined in a patient's sample, the genes being selected from a group consisting of: SEQ-ID No.1 to SEQ-ID No. 191 and are grouped in diagnostic clusters as follows: Cluster 1: SEQ-ID No.1 to SEQ-ID No. 77 Cluster 2: SEQ-ID No. 78 to SEQ-ID No.
 191. 24. The method of claim 8, characterized in that for in vitro measurement of the gene expression profiles and at least one gene activity cluster for establishing peritonitis or pneumonia of the local inflammation of a FUO, in patients, the gene activity of a plurality of certain genes or gene fragments related to peritonitis or pneumonia as the local inflammation of a FUO are determined in a patient's sample, wherein the genes or gene fragments specific for peritonitis or pneumonia are selected from the group consisting of: SEQ-ID No. 1 to SEQ-ID No. 191, gene fragments thereof with at least 20-2000 nucleotides as well as genes with a homology of sequence of at least 80%.
 25. The method of claim 9, wherein the genes or gene fragments or sequences derived from their RNA are replaced with a member selected from the group consisting of synthetic analogues, aptamers, Spiegelmers, peptido- and morpholinonucleic acids.
 26. The method of claim 8, wherein the gene activities are determined by a member selected from the group consisting of hybridisation methods, microarrays, hybridisation-independent methods, and amplification methods.
 27. Use of gene expression profiles that are obtained in vitro from a patient sample or of probes used therefore, selected from the group consisting of SEQ-ID No. 1 to SEQ-ID No. 432 as well as gene fragments thereof with at least 20 nucleotides, for determining gene activity of protein products derived therefrom for screening active agents against a member selected from the group consisting of a FUO, peritonitis and pneumonia, further wherein the gene expression profiles are used for evaluation of therapeutic effects of the active agents against the FUO, peritonitis or pneumonia.
 28. The use of claim 12, wherein the genes or gene fragments or sequences derived from their RNA are replaced with a member selected from the group consisting of synthetic analogues, aptamers, Spiegelmers, peptido- and morpholinonucleic acids.
 29. A kit containing a selection of sequences according to SEQ-ID No. 1 to SEQ-ID No. 432, which are specific for establishment of a local inflammation of a FUO, and gene fragments thereof with at least 20 nucleotides for determination of gene expression profiles in vitro in a patient's sample, for use in determination of a source of infection or a source of infection of a FUO.
 30. The kit of claim 14, further containing a selection of at least 2 polynucleotides with sequences according to SEQ-ID No. 1 to SEQ-ID No. 196 or gene fragments thereof with at least 20 nucleotides for the determination of gene expression profiles in vitro in the patient's sample, further wherein the kit is used for the establishment of peritonitis or pneumonia as the local inflammation of a FUO. 